Organic mercury compounds



Quite QRGANIC MERCURY COMPOUNDS 2,792,392 Patented May 14, E957 Louis Freedman, Mount Vernon, and Seymour L. Shapiro, 5 H

Hastings on Hudson, N. 1., assignors to U. S. Vitamin Corporation, New York, N. 1., a corporation of Dela- OCHrJJCHz-Z ware '7 GR No Drawing. Application June is, 1953, X; H Serial No. 360,825 I ll 1 l 6 z-oHPo-oHT-o-o OCH2-(l3CH2Z Claims (Cl 260 242) OR N OR This invention relates to organic mercury compounds which are novel and therapeutically useful, especially as wherein R is a lower alkyl radical, and Z Tepid-551m Hg diuretics; and relates more particularly, to such comattached a member of the grim? wllsisfing 95 OH and pounds comprising a triazine nucleus having three suba non-toxic substituent group which renders the compound stituent alhyl radicals each or which i ma ni-aired, more stable. As w1ll be pointed out later, our preferred Mercury compounds prepared by reacting un atur ted groups to be used as substituents attached to the Big are alkyl derivatives of various organic compounds with mertheOPhYHIIIe an {M110 Sulffibenzimlde -P Winch We Curio acetate to form mercuri saturated alkylated deri ahave found give the final product increased stabi ity when lives, are Well known as having diuretic properties; and the administered either orally or parenterally, as compared to prior art is probably best typified by compounds of th either the hydroxy mercuri compound or to compounds in following general formula: which the OH is substituted by other nontoxic stabilizing s H on Hg-Y grouPsl l Our new compounds have a relatively high mercurial CH2 CH" content per molecule, as compared to hereto fore known (1) (2) (3) and used products, which serves to provide a greater perwherein XNH is usually an acid amide grouo to which centage of mercury per unit of active compound; and is attached a solubilizing group S; R is a lower alkyl radisince they have a relatively high molecular weight they cal; and 15 either 01-1 or an acid radical. I T 1e X--NH afiorcl a closer approach to isotonicity at therapeutically grouping has not been ascribed as critical in serving the efiecuve levels for parenteral administration. Furtherfunction of diuresis, and has been extensively varied; the more, they are markedly b tter than the prior art coir S group usually contains a carboxyl which forms waterpounds in that our new compounds are soluble in water soluble salts, but other groups which form soluble com- Without the addition of the previously used solubilizing pounds haye bg-len used; andf the Y gffl illlli has underiroups, such as carbolilryl, which gave tgiekdisadvantage or" gone COIlSl era e variation, or examp e a i es, acetates ein precipitated in t e acid the stomach when Xanthines, thioglycollates, succinimides, and other non take; orally; whereas our compounds are neutral or toxic substituent groupings rendering the prior art comslightly acid and are readily a" roed and are better pounds more stable have been prepared. Despite all of 40 tolerated by the gastrointesti tct when adm iistered these variations, the prior art compounds are characterorally, and are less irritating and better tolerated when ized by a number of disadvantages which limit their useadministered parenterally. fulness as diuretics. For example, their inherent low Our new compounds are prepared by reacting triallyl solubility requires the incorporation of solubilizing groups cyanurate with mercuric acetate in the presence of a lower which usually render their solutions strongly alkaline, and aliphatic alcohol to form the trimercuri aliroxy acetate of further reduce their already low mercury content; so that tri-propyl cyanurate, and converting the latter. by treatthe compound is not too eificient when administered, and ment with an alkali hydroxide, to the soluble hydroxy larger doses are required. derivative, according to the following graphic equation in r p L r; E A We have discovered that these and other disadvantages which R is prererably methyl but may be ethyl or other can be overcome by forming the mercury derivatives from suitable lower alxyl radical:

O-CH2CH=CH:

N N 3Hg(C'. 302)a H l CHr=CH-CHrO-C C-O-CHz-CH- OH: ROH

(Int ([)CHrCH-CH2 /C\ HgCzHaOz 0R N Y 03 Add NaOH on on on 0 i ('3 0 on 3H on +3CH3OOOH 2 2- 2' 2 l HECZHSOI N HgCzHaOz 0R O-CH2(BHCH2 HgOH OR N N OR H l l 3CHsCOONa CHQCHCH2OC C-OC-Hz-CH-CH7 l HgOH N HgOH The following examples will serve further to explain our invention but are to be interpreted as illustrative of the invention, the scope of which will be defined in the claims hereof:

EXAMPLE 1 A solution of 20.0 g. of crystalline tri-allyl cyanurate (0.08 mole) in 250 ml. of methanol was stirred while treated portionwise with 76.5 g. (0.24 mole) of mercuric acetate, and allowed to stand overnight. Then to the clear solution was added a solution of sodium hydroxide in methanol to slight alkalinity forming the mercuri hydroxy compound as a white precipitate. This precipitate was collected by filtration, in yield of 34 g. Concentration of the methanol filtrate afforded an additional 43.5 g., for a total of 77.5 g. (or 97.5% of theoretical) yield of tri- (3 hydroxy mercuri 2 methoxy propyl) cyanurate. This compound melted at 225 C. with decomposition, and was readily soluble in water giving a solution having a neutral or slightly acid reaction. When administered intraperitoneally, 30 mg. per kg, in mice the compound showed marked diuretic activity as shown in Table 1, following.

EXAMPLE 2 A solution of 10.0 g. of crystalline tri-allyl cyanurate (0.04 mole) in 100 ml. of methanol was stirred while treated portionwise with 38.24 g. (0.12 mole) of mercuric acetate and the clear solution was allowed to stand for 92 hours. A solution of sodium hydroxide in ml. of water was added to convert the mercuri acetate compound to the hydroxy compound, the mixture was vigorously stirred, treated with 150 ml. of acetone, and filtered. The white product was washed with acetone, then ethanol, and was dried in a vacuum desiccator over phosphorus pentoxide; giving a yield of 34.4 g. (86.6% of theoretical) of a compound identical with that obtained in Example 1.

EXAMPLE 3 A solution of 20.0 g. of tri-allyl cyanurate (crystalline) (0.08 mole) in 250 ml. of ethanol was stirred while treated portionwise with 76.5 g. (0.24 mole) of mercuric acetate, and the clear solution was allowed to stand over night. To this solution was then added a solution of sodium hydroxide in 100 ml. of ethanol. The white precipitate formed was collected by filtration, with a yield of 40.3 g. (50.7% of theoretical). This product was tri-(3 hydroxy mercuri 2 ethoxy propyl) cyanurate, a white powder which melted at 250280 C. with decomposition starting at 160 C.

In the above Examples 1 to 3, we have illustrated our invention with respect to the hydroxy mercuri compounds in which the Hg is attached to OH at the positions designated as Z in the general formula given above. In the following Examples 4 to 6, we illustrate our invention with respect to our new compounds in which those hy droxyl groups are replaced by non-toxic organic substituent groups which render the compound more stable; the said substituent groups being attached to the Hg in place of the OH at the positions designated as Z in said formula. Such substituted compounds are especially effec'- tive diuretic agents in both oral and parenteral use.

EXAMPLE 4 To a warmed solution of 3.2 g. (.018 mole) of theophylline in 200 ml. water was added 6.0 g. (.006 mole) of tri-(3 hydroxy mercuri 2 methoxy propyl) cyanurate, prepared as in Example 1. The clear solution was allowed to stand over night, and was then stripped of the watergen 14.4%, as against 29.2%, 3.04%, and 14.2% respec tively, the theoretical for the compound C36H45N15012Hgs.

This product of Example 4 was soluble in water to give solutions having a neutral to slightly acid reaction, and when administered intraperitoneally, 30 mg. and 10 mg. per kg. in mice, it showed marked diuretic activity at both levels as shown in Table 1. On oral administration, the compound also showed good diuretic activity at levels ranging from 18 to 8 mg. per kg. of weight of the rats tested. Table 2, which follows Table 1, gives the diuretic index of this compound, determined by dividing the percent of urinary excretion of the animals on the test compound by the percent of urinary excretion of the animals on a physiologic saline control run simultaneously (method of Lipschitz). For comparison, the table also gives the diuretic index of 'a known diuretic compound of established activity, and urea with corresponding simultaneous controls.

Table 1 Tabulated results of diuretic activity of compounds described in Examples 1 and 4 respectively. Intraperitoneal injection in mice according to method of Greiner J. Pharm. and Expt. Therap. 103-431, 1951, wherein weight loss subsequent to administration of mercurial, reflects diuretic efficiency. Each value represents the average re Table 2.-Diuretic index comparison Diuretic Index Compound Experimental Level,

Group mgJkg.

1 hr. 2 hrs. 3 hrs.

Example 4 1-12 rats-.." 12 5.1 2. 14 1. 43

D0 2-12 rats--. 12 7. 4 1.85 1. 60

Mgcisirotphylliu 12 rats 12 1. 93 1. 33 1. 12

Urenl... do 1, 500 1. 47 1. 44 1.44

EXAMPLE 5 To a warm solution of 9.95 g. (.01 mole) of tri-(3 hydroxy mercuri 2 ethoxy propyl) cyanurate in 312 ml. water was added 5.4 g. (.03 mole) of theophylline. The solution was stirred and allowed to stand for thirty minutes and filtered from a small amount of gummy material. The clear solution was allowed to stand overnight and then stripped of the water under reduced pressure. The residue which remained was collected and dried in a vacuum desiccator over phosphorus pentoxide. A yield 'of 12.6 g. (84.4% of theory) in the form of a white powder, was obtained. The product tri-(3 theophylline mercuri 2 ethoxy propyl) cyanurate melted at 250 C. with decomposition beginning at 195 C. Analysis of nitrogen gave N=13.53%. Theory for C39H51N15012Hg3 1s N=13.8%. This product, somewhat less soluble in water than the corresponding methoxy derivative of Example 4, gives a slightly acid to neutral solution.

EXAMPLE 6 To a hot solution 1.66 g. (.00906 mole) of ortho sulfo benzimide in 50 ml. of methanol was added a solution of 3 g. (.00302 mole) of tri-(3 hydroxy mercuri 2 methoxy propyl) cyanurate, and the solution allowed to stand for 70 hours. The solvent was stripped under reduced pressure and then m1. of benzene was added and distilled off, azeotroping the residual moisture from the product.

wherein R is a member of the group consisting of methyl member of the group consisting of OH, theophylline and ortho-sulfo-benzimide.

2. The compound tri-(3-hydroxymercuri-2-methoxypro pyl) cyanurate.

3. The compound tri (3 hydroxymercuri 2- e th oxypropyl) cyanurate.

4-. The compound tri (3 theophyllinomercuri 2- methoxypropyl) cyanurate.

5. The compound tri (3 theophyllinomercun' 2- ethoxypropyl) cyanurate.

6. The compound tri-(3-[o-sulfobenzimido]mercuri-Z- methoxypropyl) cyanurate.

References Cited in the file of this patent UNITED STATES PATENTS 2,576,349 Lehman Nov. 27, 1951 OTHER REFERENCES Dominikiewica: Chem. Abst. (1936). vol. 30.

and ethyl, and in which Z represents Hg attached to a 29 p. 1030. 

1. NEW ORGANIC MERCURY COMPOUNDS WHICH ARE WATER SOLUBLE AND USEFUL AS DIURETICS, AND WHICH ARE OF THE GENERAL FORMULA 